L1

Question 1

How drugs cross the membrane?

Answer 1

• Passive diffusion
• Pinocytosis
• Aqueous pores

Question 2

Passive diffusion

Answer 2

Drugs must be sufficiently hydrophobic to penetrate membranes but then pass through the aqeuous intracellular env and not be trapped in the membrane.

Question 3

What is Fick’s Law?

Answer 3

Simple diffusion if dependent on the permeability of the membrane and the conc. gradient
- The rate at which the drug will diffuse through the membrane is dependent on the conc.

Question 4

Pinocytosis

Answer 4

Pinching off membrane relevant for several protein drugs

Question 5

Aqueous pores

Answer 5

Small drugs are able to pass through

Question 6

Importance of drug ionisation

Answer 6

Ionisation influences the extent of drug movement between aqueous env. and lipid env.

Strong acids/ bases ionised at any pH - but these are few drugs

Weak acids and bases- extent of ionisation depends on pH of aqueous env. E.g. for a weakly acidic drugs in an acidic env. will suppress ionsiation, thus will favour diffusion through a membrane

Question 7

Ionised or neutral form prefered

Answer 7

neutral is favoured and moves across membrane. Thus pH can influence the relative conc. of the neutral form of the drug

Question 8

How does tissue pH affect drug disposition

Answer 8

E.g. aspirin (pH 3.5)
stomach 2.2 and intestine of 7..5
Aspirin would be neutral in the stomach and thus penetrate through the membrane. However in the small intestines, aspirin would be ionised thus absorption would not be favoured.

Question 9

Influx transporters

• Solute carrier transports
• structure

Answer 9

• main role is transport anions and cations across membranes
• also mediate uptake many drugs
  Structure:
• consists of 12-transmembrane domains
• several intracellular and extracellular loops that orient the transporter in the membrane

Question 10

Bioavailability

Answer 10

the amount of drug that is able to produced inside the body after administration and reaches the systemic circulation
intravenous dose is 1

Question 11

Oral

- two mechanisms

Answer 11

bioavailability is decreased, drug is not absorbed

• First pass clearance (liver)
• presystemic metabolism in intestine

Question 12

First pass hepatic clearance

Answer 12

Drug is absorbed in the portal circulation –> liver

• Liver is where biotransformation occurs
• Blood in portal vein before liver is conc. however after the drug is less conc. thus less will get in circulation
• Hepatic extraction is high when drug is extensively metabolised

Question 13

Presystemic metabolism in intestine

Answer 13

Enterocytes contain biotransformation enzymes which are able to begin the process of the drug degradation
- after passing through the enterocyte, conc. of the drug will be reduces as the drug has been extensively metabolised.

Question 14

Methods which avoid first-pass clearance

Answer 14

• Eyedrops
• Sublingual
• rectal adminsitration
• dermal delivery

This is because these methods tend to bypass the liver before reaching their target

Question 15

Protein binding - can free drugs or drug-protein complex move across

Answer 15

only free drugs can move across

Question 16

Plasma protein binding and free fraction of drug

Answer 16

• plasma proteins limit the free drug conc.
• these proteins bind loosely to the drug before entering system
• 1% of drug is in free form
• only free drugs can move across membrane

Question 17

Protein binding to drug - Serum albumin

Answer 17

in some liver diseases, the albumin synthesis is decreased, thus less protein are binding to the drug. Thus more free form of the drug is able to move across. Thus instead 1% of drug being absorbed, there will be 5% which increases the dose of the drug and can be toxic.

Question 18

A1-acidglycoprotein (AAG) bind to basic drugs

Answer 18

An inflammatory disease can cause production of more AAG, thus more AAG binding to the drug, thus less free form. Hence less is able to be absorbed thus drug is not as effective.

Question 19

Bioavailability

Answer 19

AUC oral/ AUC intravenous

Question 20

Cmin define

Answer 20

conc. of drug within limits during therapy

Question 21

Biotransformation does what to lipophilicity

Answer 21

decreases. But at the same time increases water solubility

Question 22

How does the body eliminate drugs? Simple answer

Answer 22

Biotransformation enzymes convert the lipid soluble chemicals to soluble chemicals (more polar), thus easily eliminated. Some metabolities are less active but some drugs are prodrugs that require metabolic activation.

Question 23

Lipophillic character of drug

Answer 23

• Drugs must be lipophilic to penetrate membranes

- thus a drug will have lipid-like and aqueous phases

Question 24

Partition coefficient (P)

Answer 24

the ratio of conc. in the lipid/ aqueous phase

Question 25

where does biotransformation occur

Answer 25

mainly liver but also can occur in lungs, kidney, intestine, skin

Question 26

Phase I reactions

Answer 26

convert lipophlic chemical into a more polar substance. Thus through oxidation, reduction or hydrolysis get a new functional group

Question 27

Cytochromes P450 (CYPs)

Answer 27

The major class of phase I biotransformation enzymes

Question 28

What do Cytochromes P450 act on?

Answer 28

diverse substrates (low substrate specificity)

Question 29

Structure of CYP

Answer 29

• have a haem group involved in oxygen activation
• the polypeptide chain differs between CYPS and control substrate specificity
• Each CYP is encoded by a different gene
• The variation in the AA will influence function of enzyme